Myeloproliferative Syndromes Flashcards
1
Q
How do platelets form?
A
- HSC
- myeloid progenitor cell
- megakaryocyte
- megakaryoblast
- promegakaryoblast
- megakaryocyte
- platelets
2
Q
How do RBCs form?
A
- HSC
- myeloid progenitor cell
- erythroid progenitor
- proerythroblast
- erythroblast
- reticulocyte
- RBCs
3
Q
How do mast cells form?
A
Directly from common myeloid progenitor cells
4
Q
What are the main MPN?
A
- chronic myelogenous leukaemia
- polycythemia vera
- essential thrombocytopenia
- primary myelofibrosis
5
Q
What type of genetic conditions are MNP?
A
Acquired
6
Q
What are the characteristics of CML?
A
- uncontrolled mature granulocytic proliferation
- 9,22 Philadelphia chromosome present
- long chromosome 9 and short 22
- men more common
- 50 years common
- increased granulocytes in all stages of maturation unlike acute which are all mature blasts
7
Q
Presentation of CML
A
Systemic - fatigue - night sweats - malaise - weight loss Splenomegaly - early satiety - L. upper quadrant pain Hyper viscosity - headache/blurred vision - fluid overload - thrombosis and haemorrhage
8
Q
When can CML become AML?
A
in the blast phase
9
Q
Diagnosis of CML?
A
- raised WCC
- basophilia
- blood film
- bone marrow biopsy
- G banding
- FISH
- Reverse transcriptase PCR (quantitative, telling you how many BCR-ABL)
- Low NAP/LAP score (alkaline phosphatase score)
10
Q
What is the hallmark of chronic myeloid leukaemia?
A
Philadelphia chromosome
- also occurs in AML
- shortened chromosome 22 and longer 9
- due to translocation
- causes fusion of BCR and ABL genes
11
Q
What does BCR-ABL code for?
A
- encodes tyrosine kinase which becomes constitutively active = uncontrolled cell division and inhibits DNA repair = genetic instability
12
Q
How is CML treated?
A
- imatinib (1st generation) and 2nd/3rd generation TKIs
- some don’t respond so chemotherapy or if progressed to AML
- cure with allogeneic HSC transplant sometimes
13
Q
Prognosis of CML?
A
- increased LE
- good
14
Q
What is primary polycythaemia vera?
A
- increased RBC volume as clonal malignancy of marrow stem cell
- all 3 cell lines can be increased (white and platelets)
- otherwise unexplained high haematocrit so need to rule out other causes
- usually from JAK2 mutation
- age 60 common
15
Q
What is the significance of haematocrit in polycythaemia vera?
A
- % of total blood volume is made from RBCs
- normal is 55%
- raised in PV due to increased RBC volume only
- increased by increased RBC or reduced plasma due to dehydration so need to rule this out
16
Q
Requirements for polycythaemia vera diagnosis?
A
Increase in haematocrit due to increase in % of RBC volume
- males > 0.6
- females > 0.56
raised for more 2 months
Hb > 18.5 in males and 16.5 in females
17
Q
Other causes of raised haematocrit/polycythaemia
A
Relative = apparent/reduced plasma volume due to dehydration
True = absolute due to increase in RBC
- can be true primary where EPO is low or normal= PV
- true secondary is overproduction of EPO
18
Q
Causes of true secondary polycythaemia
A
Hypoxic driven - high altitude - cardiopulmonary disease - defective oxygen transport Hypoxia independent - renal cysts/ tumours - extrarenal tumors - exogenous EPO/drugs
19
Q
Presentation of polycythaemia vera
A
- asymptomatic for many
- plethoric appearance (red)!
- post bath puritis (aquagenic puritis)!
- splenomegaly
- acute gout
- headache
- erythromelalgia (occlusion of vessels in fingers)
- thrombosis !
- haemorrhage
20
Q
Diagnosis of PV (stage 1)
A
- history
- examination
- FBC (elevated Hb and Hc o no other cause)
- ferritin will be low as making lots of RBCs so iron deficiency
- JAK2 mutation for definitive test
- renal and liver function
21
Q
Why don’t you give iron in PV?
A
Will make even more RBCs which don’t need
May mask erythrocytosis
22
Q
What is the role of JAK2 in PV?
A
- intracellular protein and TKR
- attached to EPO receptor
- EPO binds to receptor activating JAK2
- activates JAK2 IC pathway
- allows proliferation and survival of cell to make more RBC
- if mutated = constitutively active protein so uncontrolled RBC proliferation
23
Q
Diagnosis of PV (stage 2)
A
- Low serum EPO
- arterial SO2 to look for 2ndry causes
- abdom US for splenomegaly or renal tumour
- bone marrow biopsy
- red cell mass study (determines true or relative erythrocytosis)
24
Q
Prognosis of PV
A
10-16 years survival Cardiovasc events Thrombosis Progression to myelofibrosis Progression to AML like all MPNs 2ndry haemorrhage in all MPNs
25
Treatment of PV?
- venesection is HCT <0.45
- aspirin
- myelosuppressive drugs (hydroxycarbamide, interferon, busulphan)
- JAK inhibitors
26
What is essential thrombocythaemia
- sustained increase in platelet count as megakaryocytic proliferation
- define by ruling out all other causes of raised platelet count
- not morphologically or cytogenetically defined
- more common in females
- 60 years
- overall good survival 10 years
27
Presentation of thrombocythaemia
- asymptomatic mainly
- thrombosis arterial and venous
- haemorrhage as poor platelet function
- erythromelalgia
- splenomegaly
- fatigue/malaise/weight loss
28
What are secondary causes of raised platelet count?
- chronic infection
- chronic inflammation
- iron deficiency
- haemorrhage response
- hyposplenism
- malignancy
- drugs (steroids)
- exclude other myeloid malignancy
29
How to diagnose thrombocythemia?
- JAK2 mutation common
- CALR and MPL mutations sometimes
- bone marrow biopsy = elevated megakaryocytes
30
Prognosis of thrombocythemia
- 10 year survival
- risk of thrombosis and bleeding
- transformation MF and AML
31
Treatment of thrombocythemia
- all patients on aspirin
| - myelosuppressive drugs (hydroxycarbamide - especially if thrombosis before to normalise platelet count)
32
Why are venesections not practical for thrombocythemia?
platelets life is only 7-10 days so will have to keep doing them
33
What is myelofibrosis?
- clonal stem cell malignancy
- primary = on its own
- secondary = progression from other MPN
- bone marrow replaced by scar tissue (fibrosis) which is stimulated by abnormal megakaryocytes
- untreated -> raise in blood count initially but then eventually drop -> AML eventually
- JAK2 common, CALR, MPL
34
Presentation of myelofibrosis
- fatigue
- weight loss
- night sweats
- raised WCC initially then drop
- progressive cytopenias
- massive splenomegaly
- extramedullary haematopoiesis as spleen takes over making it massive
35
Characteristic of myelofibrosis blood film
- teardrop poikilocytes (abnormal shape) and leucoerythroblastic (white and nucleated red blasts)
36
Bone marrow biopsy in myelofibrosis
- increase in fibrosis so increased reticulin
- streaming (architecture disrupted)
- increased cellularity
37
Diagnosis of myelofibrosis
- bone marrow reticulin fibrosis
- splenomegaly
- anaemia
- teardrop poikilocytes and leucoerythroblastic blood film
- JAK2 mutation, CALR, MPL
38
Treatment of myelofibrosis
- dependent on risk
- poor prognosis as AML progression risk
- stratify risk based on age and blast count
- transfusion for supportive management
- splenectomy
- if high risk = allogeneic SC transplant
- JAK inhibitors (ruxolitinib)
- hydroxycarbamide control high cell counts
- andorgens (anabolic steroids stimulate bone marrow improving low bloow count)
39
Prognosis of myelofibrosis
- poor overall
- 1 year survival if high risk
- 12 years if low risk
- risk factors = age, blast, transfusion dependence, cytogenetics
- progression to AML being main reason
